The present application is related to Merck 18996, U.S. Ser. No. 08/059,038, filed May 7, 1993, and Merck case 19115, U.S. Ser. No. 08/212,604, filed Mar. 11, 1994.
The present invention is concerned with a novel intermediate and process for synthesizing compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as compound J in the Examples below. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
The invention described herein concerns a process to effect the regiospecific generation of a cis-1-amino-2-alkanol, particularly cis-1-amino-2-indanol (Compound B), from an epoxide precursor. More specifically, the stereochemical integrity of the carbon-oxygen bond at C-2 in the indene oxide., starting material is retained, so that there is substantially complete ,conversion to the appropriate product 1-amino-2-indanol. For example, (1S,2R)-indene oxide produces substantially 1S-amino-2R-indanol, and (1R,2S)-indene oxide produces substantially 1R-amino-2S-indanol. Mixtures of epoxide enantiomers produce substantially the same mixture of 1-amino-2-indanol enantiomers. The process described is superior to prior art in that the process is shorter, more productive, and has higher yields with less environmental impact.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313,277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. The end product compounds, including certain oligopeptide analogs that can be made from the novel intermediates and processes of this invention, are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993. See, for example, compound J therein.
Previously., the synthesis of Compound J and related compounds was accomplished via a 12-step procedure. This procedure is described in EPO 541,168. The extreme length of this route (12 steps), renders this process time consuming and labor intensive, and it requires the use of many expensive reagents and an expensive starting material. A route requiring fewer reaction steps and reagents would provide desirable economical and time-saving benefits.
Specifically, the invention provides a process for the synthesis of 1S-amino-2R-indanol (Compound B) from (1S,2R)-indene ##STR1## oxide (Compound A). The epoxide A is treated with a strong acid and a nitrile, then hydrolyzed with water to give the target Compound B. The process of the present invention is a one step procedure, and avoids isolation of any intermediate.
The preparation of 1-amino-2-indanol was previously accomplished via a multistep sequence. This sequence involved the treatment of an indene oxide with aqueous ammonia to produce a trans-1-amino-2-indanol (Cpd C). ##STR2## The intermediate C is then treated with an acyl halide, thereby converting the amine to an amide intermediate (Cpd D). The hydroxyl group of the hydroxy amine D is activated by conversion to a mesylate (Cpd E), which is then induced to cyclize and form the oxazoline F. The oxazoline F produced by this prior art method is purified, then subjected to conditions similar to that described above effecting its conversion to the target cis-1-amino-2-indanol.
In previous attempts, epoxides are reported to give only poor yields of regioisomeric oxazolines when subject to the conditions of strong acid/nitrile solvents. See R. Bishop, "Comprehensive Organic Synthesis," ed. B. M. Trost et al., Pergamon Press. New York, 1991, vol. 6 p. 276; R. Oda, et al., Bull. Chem. Soc. Jpn., 35, 1219 (1962).
Contrary to the present invention, steroidal epoxides when treated with acid and a nitrile are reported to produce transdiaxial alpha amido alcohols and not oxazolines [G. Bourgery, et al., Tetrahedron, 28, 1377 (1972); R. J. Ryan etal., Tetrahedron, 29, 3649 (1973)].
Also contrary to the present invention, methyl-trans-2-epoxystearate is reported to produce an erythro-beta amino-alcohol and not an oxazoline [E. N. Zvankova and R. P. Evstigneeva, Zh. Org. Khim., 10, 878, (1974)].
Thus related art teaches that treatment of an epoxide under the conditions described by this invention would not only be expected to produce low yields but also the wrong product.
The process of the present invention provides a route with fewer chemical steps to accomplish the same overall synthesis of 1S-amino-2R-indanol. Furthermore, the isolation of intermediates is not necessary in the present invention. Also, the present process utilitizes smaller quantities of organic solvents and proceeds in greater overall yield than prior methods, a result providing lower environmental impact than prior methods.